Alterations of insulin receptor concentration and affinity appear to play a major role in a number of states of insulin resistance and diabetes mellitus, yet little is known about the mechanism of receptor modulation. I plan to study the insulin receptor and other hormone receptors during the process of in vitro differentiation. My plan is to study the insulin binding properties of the Friend Erythroleukemia cell line, which is a model system for erythropoiesis. These cells differentiate in vitro from cells resembling basophilic erythroblasts, very early red cell precursors, to cells resembling orthochromic mormocytes, differentiated red cells containing hemoglobin. We have shown that the early precursor forms contain about 15,000 insulin receptors per cell and that during the process of differentiation insulin receptors are lost, so that the later forms have only about 6,000 receptors per cell. I plan further studies of the properties of the receptors in both the precursor and differentiated cells as well as studies on effects of other factors such as hyperinsulinism and the cell cycle on the process of differentiation. Our plans, of course, include a comparison of insulin sensitive functions in these cells with the alterations in insulin receptor concentration.